For many conditions, such as dyspepsia, asthma, headache and arthritis, it is often difficult to judge whether an observed improvement in a patient's symptoms results from pharmacological treatment or a placebo effect, or is a spontaneous event. To overcome this problem; Single Subject Trials (N-of-1 trials) were designed. These have a long tradition of use in psychology and psychiatry, but the early studies were often non-randomised and the evaluation of the observations was largely subjective. In the 1980s, single subject trials were re-introduced to assist in decisions on a drug's efficacy in the treatment of an individual patient. The design of the trial was refined, and in the revised design the patient is given an active drug and placebo in randomised order in a double-blind cross-over manner for a series of consecutive periods (of up to 1 week). The judgement of the drug's efficacy is based on a comparison of symptoms during active treatment periods with those during placebo periods.
There are, however, some statistical problems and weakness associated with this design of trial. Inferential problems of the multiple cross-over design emanate from two sources: observations from adjacent periods are likely to be auto-correlated (i.e. more similar than observations that are more distant in time) and carry-over effects from the preceding period are not uncommon. Thus the basic and fundamental assumption of independence between observations that underlies most statistical methods is likely to be more or less violated, and there is an increased risk of significance tests and confidence intervals resulting in false conclusions.
Furthermore, a Single Subject Trial with multiple cross-over design is not suitable for testing the efficacy of drugs with a long duration of action (i.e. several days), because it necessitates the inclusion of wash-out periods, which prolongs the trial. The trial length may be critical for conditions with spontaneous variations in disease activity.
In an attempt to overcome these problems, a novel alternative, The Random Starting Day (RSD) trial, has been designed and briefly described in an abstract presented at the World Congress of Gastroenterology, Oct. 2-7,1994. According to said abstract the basic principle of the RSD trial is as follows: The patient starts on placebo and, on a randomly chosen day, switches to the active drug for the remainder of the trial period. The day for switching is randomly determined and varies between patients, and it is known neither to the patient nor the investigator or physician.